Study of the role of alpha-synuclein phosphorylation at Ser 129 in dopaminergic neurodegeneration in parkinsons disease

Studies during the last decade have established a central role in Parkinson’s disease (PD) neurodegeneration for the protein alphasynuclein (α-syn). Among the different post-translational modifi - cations that human a-syn can undergo, phosphorylation has been related to the disease. α-syn phosphorylation at Ser 129 seems to be related to the disease progress in PD, since S129P-α-syn is found in low levels in healthy humans and it is related to increased inclusion formation. In order to elucidate the role of phosphorylation of α-syn at Ser 129 in the disease process we used a rat PD model based on the local injection of recombinant adeno-associated viral vectors (rAAV). We created mutations in α-syn at Ser129, replacing the serine either with alanine (S129A) to block phosphorylation or with aspartate (S129D) to mimic phosphorylation. We overexpressed wt, S129A and S129D α-syn in rat midbrain and thereafter have compared the effect of the overexpression on dopaminergic neurons at different time points post-injection. Our results show that pseudophosphorylated α-syn S129D induced faster motor defi cit compared to S129A. On our hands, the phosphorylation of α-syn at Ser129 seems to have a role in the progression of the disease but is not necessary for pathology, motor defi cits or cell death to occur.